The aim of the proposed research is to characterize large molecule (greater than 1.5nm radius) transport across the capillary wall. Single capillary studies have begun to clarify the basic physicochemical nature of the pathways for small solutes (less than 0.5nm radius) and water but not for large molecules. Whole organ studies of large molecule transport suggest that greater than 50% of macromolecular flux occurs across a large pore pathway. It is not known if this pathway exists in all capillaries or is confined to venous or postvenous capillaries. Recent advances in single capillary methodology, in this laboratory, suggest that the large pore pathway can be experimentally verified. The specific aims of the proposed study are to 1) measure large molecule flux under conditions where transcapillary pressure difference, DeltaP, and osmotic pressure difference, DeltaPi, are known on single capillaries, 2) use these results to calculate capillary permeability (P), 3) investigate the physicochemical nature of the large molecule pathway by measuring macromolecular P for perfusates having a range of chemical composition and 4) test if a correlation of capillary type and macromolecular permeability exists. The studies in this proposal will experimentally distinguish between two hypotheses: 1) Under normal conditions of fluid balance diffusion alone accounts for the observed flux of macromolecules, and 2) Under normal conditions diffusion and solvent drag account for the observed macromolecular flux. These studies will provide the most direct route to an experimental test of these hypotheses. Both short and long term fluid balance depend on the distribution of macromolecules between vascular and extravascular spaces. Capillary wall integrity is compromised under several clinical conditions of trauma, edema, and inflammation. In these states large molecules and water, normally retained in the vasculature, leak into the surrounding tissue leading to loss of organ function. Clarification of the physical nature of the pathways normally available to large solutes will provide the basic information necessary to initiate clinical evaluation of life threatening conditions of pulmonary edema, venous congestion, and shock.